Drug targets. Relationship between the biological activity of drugs and their structure The main targets of the molecular structure under exposure

Pharmacodynamics is a section of clinical pharmacology that studies the mechanisms of action, the nature, strength and duration of the pharmacological effects of drugs used in clinical practice.

Ways of exposure to drugs on the human body

Most drugs, when binding to receptors or other target molecules, form a "drug-receptor" complex, which triggers certain physiological or biochemical processes (or their quantitative change) in the human body. In this case, we talk about the direct action of drugs. The structure of a direct-acting drug, as a rule, is similar to the structure of an endogenous mediator (however, different effects are often recorded during the interaction of a drug and a mediator with a receptor).

Groups of medicines

For convenience, let us take the value of the effect of the endogenous mediator binding to the receptor equal to unity. There is a classification of drugs based on this assumption.

Agonists are drugs that bind to the same receptors as endogenous mediators. Agonists produce an effect equal to one (or more than one).

Antagonists - drugs that bind to the same receptors as endogenous mediators; do not have any effect (in this case, they say "zero effect").

Partial agonists or agonist-antagonists are drugs that bind to the same receptors as endogenous mediators. The effect recorded during the interaction of a partial agonist with a receptor is always greater than zero, but less than one.

All natural mediators are agonists of their receptors.

Often, an indirect effect is noted, consisting in a change in the activity of target molecules under the influence of drugs (thus affecting various metabolic processes).

Drug target molecules

A drug, binding to a target molecule belonging to a cell (or located extracellularly), modifies its functional status, leading to an increase, weakening or stabilization of phylogenetically determined reactions of the body.

Receptors.

- Membrane (receptors I, II and III types).

- Intracellular (type IV receptors).

Non-receptor target molecules of the cytoplasmic membrane.

- Cytoplasmic ion channels.

- Nonspecific proteins and lipids of the cytoplasmic membrane.

Immunoglobulin target molecules.

Enzymes.

Inorganic compounds (eg hydrochloric acid and metals).

Target molecules have complementarity to endogenous mediators and corresponding drugs, which consists in a certain spatial arrangement of ionic, hydrophobic, nucleophilic, or electrophilic functional groups. Many drugs (first generation antihistamines, tricyclic antidepressants, and some others) can bind to morphologically similar but functionally different target molecules.

Types of bonds of drugs with target molecules

The weakest bonds between a drug and a target molecule are van der Waals bonds due to dipole interactions; most often determine the specificity of the interaction of the drug and the target molecule. Hydrophobic bonds characteristic of drugs with a steroid structure are stronger. The hydrophobic properties of glucocorticosteroid hormones and the lipid bilayer of the plasma membrane allow such drugs to easily penetrate through the cytoplasmic and intracellular membranes into the cell and nucleus to their receptors. Even stronger hydrogen bonds are formed between the hydrogen and oxygen atoms of neighboring molecules. Hydrogen and van der Waals bonds arise in the presence of complementarity between drugs and target molecules (for example, between an agonist or antagonist and a receptor). Their strength is sufficient for the formation of the LS-receptor complex.

The strongest bonds are ionic and covalent. Ionic bonds are formed, as a rule, between metal ions and strong acid residues (antacids) during polarization. When a drug and a receptor are connected, irreversible covalent bonds occur. Antagonis-

you irreversible action bind to receptors covalently. Of great importance is the formation of coordination covalent bonds. Stable chelate complexes (for example, the combination of a drug and its antidote, unithiol*, with digoxin) is a simple model of a covalent coordination bond. When a covalent bond is formed, the target molecule is usually "turned off". This explains the formation of a persistent pharmacological effect (the antiplatelet effect of acetylsalicylic acid is the result of its irreversible interaction with platelet cyclooxygenase), as well as the development of some side effects (ulcerogenic effect of acetylsalicylic acid is a consequence of the formation of an inextricable link between this drug substance and cyclooxygenase of cells of the gastric mucosa).

Non-receptor target molecules of the plasma membrane

Drugs used for inhalation anesthesia are an example of drugs that bind to non-receptor target molecules of the plasma membrane. Means for inhalation anesthesia (halothane, enflurane *) non-specifically bind to proteins (ion channels) and lipids of the plasma membrane of central neurons. There is an opinion that as a result of such binding, drugs disrupt the conductivity of ion channels (including sodium channels), leading to an increase in the threshold of the action potential and a decrease in the frequency of its occurrence. Means for inhalation anesthesia, connecting with the elements of the membranes of the central neurons, cause a reversible change in their ordered structure. This fact is confirmed by experimental studies: anesthetized animals quickly exit the state of general anesthesia when they are placed in a hyperbaric chamber, where membrane disturbances are restored.

Non-receptor plasma structures (voltage-gated sodium channels) also act as target molecules for local anesthetics. Drugs, binding to voltage-dependent sodium channels of axons and central neurons, block the channels, and thus disrupt their conduction for sodium ions. As a result, there is a violation of cell depolarization. Therapeutic doses of local anesthetics block the conduction of peripheral nerves, and their toxic amounts also depress central neurons.

Some drugs lack their target molecules. However, such drugs function as substrates for many metabolic reactions. There is the concept of "substrate action" of drugs:

they are used to compensate for the lack of various substrates necessary for the body (for example, amino acids, vitamins, vitamin-mineral complexes and glucose).

Receptors

Receptors are protein macromolecules or polypeptides, often associated with polysaccharide branches and fatty acid residues (glycoproteins, lipoproteins). Each drug can be compared with a key that fits its own lock - a specific receptor for this substance. However, only a portion of the receptor molecule, called the binding site, represents a keyhole. The drug, when combined with the receptor, potentiates the formation of conformational changes in it, leading to functional changes in other parts of the receptor molecule.

A typical receptor scheme includes four steps.

Binding of drugs to a receptor located on the cell surface (or intracellularly).

Formation of a drug-receptor complex and, consequently, a change in the conformation of the receptor.

Transmission of a signal from the LS-receptor complex to the cell through various effector systems that amplify and interpret this signal many times over.

Cellular response (fast and delayed).

There are four pharmacologically significant types of receptors

Receptors - ion channels.

G-protein coupled receptors.

Receptors with tyrosine kinase activity.

intracellular receptors. Membrane receptors

Receptors of types I, II and III are built into the plasma membrane - transmembrane proteins in relation to the cell membrane. Type IV receptors are located intracellularly - in the nucleus and other subcellular structures. In addition, immunoglobulin receptors, representing glycoprotein macromolecules, are isolated.

Type I receptors have the appearance and structure of ion channels, have binding sites with a specific drug or mediator that induces the opening of an ion channel formed by the receptor. One of the representatives of type I receptors, the N-cholinergic receptor, is a glycoprotein consisting of five transmembrane polypeptide subunits. There are four types of subunits - α, β, γ and δ type. The glycoprotein contains one subunit of β, γ and δ type and

two α subunits. Transmembrane polypeptide subunits have the form of cylinders penetrating the membrane and surrounding a narrow channel. Each type of subunit encodes its own gene (however, genes have significant homology). Acetylcholine binding sites are localized at the "extracellular ends" of the α-subunits. When drugs bind to these sites, conformational changes are observed, leading to channel expansion and facilitation of sodium ion conductivity, and, consequently, to cell depolarization.

Type I receptors, in addition to the N-cholinergic receptor, also include the GABA A receptor, glycine and glutamate receptors.

G-protein coupled receptors (type II) are the most numerous group of receptors found in the human body; perform important functions. Most neurotransmitters, hormones, and drugs bind to type II receptors. The most common cellular receptors of this type include vasopressin and angiotensin, α-adrenoreceptors, β-adrenoreceptors and m-cholinergic receptors, opiate and dopamine, adenosine, histamine and many other receptors. All of the above receptors are targets of drugs that make up extensive pharmacological groups.

Each type 2 receptor is a polypeptide chain with an N-terminus (located in the extracellular environment) and a C-terminus (located in the cytoplasm). At the same time, the polypeptide chain of the receptor penetrates the plasma membrane of the cell seven times (it has seven transmembrane segments). Thus, the structure of a type II receptor can be compared to a thread that alternately stitches the tissue from both sides seven times. The specificity of various type 2 receptors depends not only on the amino acid sequence, but also on the length and ratio of the “loops” that protrude out and into the cell.

Type II receptors form complexes with membrane G proteins. G proteins are made up of three subunits: α, β, and γ. After binding of the receptor to the drug, a drug-receptor complex is formed. Then conformational changes occur in the receptor. G-protein, binding one or two subunits to its "targets", activates or inhibits them. Adenylate cyclase, phospholipase C, ion channels, cyclic guanosine monophosphate (cGMP)-phosphodiesterase - G-protein targets. Typically, activated enzymes transmit and amplify the "signal" through second messenger systems.

Receptors with tyrosine kinase activity

Receptors with tyrosine kinase activity (type III) - receptors for peptide hormones that regulate growth, differentiation and

development. Peptide hormones include, for example, insulin, epidermal growth factor, platelet growth factor. As a rule, the binding of the receptor to the hormone activates tyrosine protein kinase, which is the cytoplasmic part (domain) of the receptor. The target of protein kinase is a receptor with the ability to autophosphorylate. Each polypeptide receptor has one transmembrane segment (domain).

However, studies have shown that not tyrosine protein kinase, but guanylate cyclase, which catalyzes the formation of the secondary messenger cGMP, performs the functions of the cytoplasmic domain of the atrial natriuretic peptide receptor.

intracellular receptors

Intracellular receptors (type IV) include glucocorticosteroid and thyroid hormone receptors, as well as retinoid and vitamin D receptors. The group of intracellular receptors includes receptors not associated with the plasma membrane, localized inside the cell nucleus (this is the main difference).

Intracellular receptors are soluble DNA-binding proteins that regulate the transcription of certain genes. Each type IV receptor consists of three domains - hormone-binding, central and N-terminal (the domain of the N-terminus of the receptor molecule). These receptors qualitatively and quantitatively regulate the level of transcription of a certain “set” of genes specific for each receptor, and also cause a modification of the biochemical and functional status of the cell and its metabolic processes.

Receptor effector systems

There are various ways of transmitting signals formed during the functioning of receptors to the cell. The signal transduction pathway depends on the type of receptor (Table 2-1).

The main second messengers are cyclic adenosine monophosphate (cAMP), calcium ions, inositol triphosphate, and diacylglycerol.

Immunoglobulins (immunoglobulin receptors)

With the help of immunoglobulin receptors, cells have the ability to "recognize" each other or antigens. As a result of the interaction of receptors, adhesion of a cell to a cell or a cell to an antigen occurs. This type of receptor also includes antibodies that freely circulate in extracellular fluids and are not associated with cellular structures. Antibodies, "marking" antigens for subsequent phagocytosis, are responsible for the development of humoral immunity.

Table 2-1. Receptor effector systems

Receptor type Receptor example Signaling methods

The type of immunoglobulins includes receptors that perform the function of "signaling" in the formation of various types and phases of the immune response and immune memory.

The main representatives of the immunoglobulin-type receptors (superfamily).

Antibodies - immunoglobulins (Ig).

T-cell receptors.

Glycoproteins MHC I and MHC II (Major Histocompatibility Complex major histocompatibility complex).

Cell adhesion glycoproteins (eg CD2, CD4 and CD8).

Some polypeptide chains of the CD3 complex associated with T-cell receptors.

Fc receptors located on various types of leukocytes (lymphocytes, macrophages, neutrophils).

The functional and morphological isolation of immunoglobulin receptors makes it possible to distinguish them into a separate type.

Enzymes

Many drugs, binding to enzymes, reversibly or irreversibly inhibit or activate them. Thus, anticholinesterase agents enhance the action of acetylcholine by blocking the enzyme that breaks it down - acetylcholinesterase. Carbonic anhydrase inhibitors are a group of diuretics that indirectly (under the influence of carbonic anhydrase) reduce the reabsorption of sodium ions in the proximal tubules. NSAIDs are cyclooxygenase inhibitors. However, acetylsalicylic acid, unlike other NSAIDs, irreversibly blocks cyclooxygenase by acetylation of serine (amino acid) residues in the enzyme molecule. There are two generations of monoamine oxidase inhibitors (MAOIs). MAO inhibitors - drugs belonging to the group of antidepressants. First-generation MAO inhibitors (such as phenelzine and isocarboxazid) irreversibly block the enzyme that oxidizes monoamines such as norepinephrine * and serotonin (their deficiency is found in depression). A new generation of MAO inhibitors (for example, moclobemide) reversibly inhibits the enzyme; at the same time, less severity of side effects (in particular, "tyramine" syndrome) is noted.

inorganic compounds

There are drugs that directionally neutralize or bind the active forms of various inorganic compounds. So, antacids neutralize excess hydrochloric acid of gastric juice, reduce

Shaya its damaging effect on the mucous membrane of the stomach and duodenum.

Chelating substances (complexons) combine with certain metals to form chemically inert complex compounds. This effect is used in the treatment of poisoning caused by ingestion (or inhalation) of substances containing various metals (arsenic, lead, iron, copper).

Target molecules located on foreign organisms

The mechanisms of action of antibacterial, antiprotozoal, anthelmintic, antifungal and antiviral drugs are very diverse. Taking antibacterial drugs, as a rule, leads to a violation of various stages of the synthesis of the bacterial cell wall (for example, to the synthesis of defective proteins or RNA in a bacterial cell) or a change in other mechanisms for maintaining the vital activity of the microorganism. Suppression or eradication of the infectious agent is the main goal of treatment.

The mechanism of the bactericidal action of β-lactam antibiotics, glycopeptides and isoniazid is the blockade of various stages of the synthesis of the cell wall of microorganisms. All β-lactam antibiotics (penicillins, cephalosporins, carbapenems and monobactams) have a similar principle of action. Penicillins produce a bactericidal effect by binding to penicillin-binding proteins of bacteria (they act as enzymes at the final stage of the synthesis of the main component of the bacterial cell wall - peptidoglycan). The commonality of the mechanism of action of β-lactam antibiotics is to create obstacles to the formation of bonds between the polymer chains of peptidoglycans using pentaglycine bridges (part of the structure of antibacterial drugs resembles the D-alanyl-D-alanine-peptide chain of the bacterial cell wall). Glycopeptides (vancomycin and teicoplanin*) interfere with cell wall synthesis in a different way. Thus, vancomycin has a bactericidal effect by combining with the free carboxyl group of the pentapeptide; thus, there is a spatial obstacle

vie elongation (lengthening) of the peptidoglycan tail. Isoniazid (an anti-tuberculosis drug) inhibits the synthesis of mycolic acids, a structural component of the mycobacterial cell wall.

The mechanism of the bactericidal action of polymyxins is to disrupt the integrity of the cytoplasmic membrane of bacteria.

Aminoglycosides, tetracyclines, macrolides and levomycetin* inhibit protein synthesis in bacterial cells. Bacterial ribosomes (50S subunits and 30S subunits) and human ribosomes (6OS subunits and 40S subunits) have different structures. This explains the selective effect of these groups of medicinal substances on microorganisms. Aminoglycosides and tetracyclines bind to the 30S subunit of the ribosome and inhibit the binding of aminoacyltRNA to the A site of this tRNA. In addition, aminoglycosides interfere with mRNA reading by blocking protein synthesis. Levomycetin * changes the process of transpeptidation (transfer of a growing amino acid chain on the ribosome from the P-site to the A-site to the newly brought tRNA amino acids). Macrolides bind to the 50S subunit of the ribosome and inhibit the translocation process (transfer of an amino acid chain from the A site to the P site).

Quinolones and fluoroquinolones inhibit DNA gyrase (topoisomerase II and topoisomerase IV) - enzymes that help twist bacterial DNA into a spiral, which is necessary for its normal functioning.

Sulfonamides inhibit dihydropteroate synthetase, thereby blocking the synthesis of purine and pyrimidine precursors (dihydropteric and dihydrofolic acids) necessary for building DNA and RNA. Trimethoprim inhibits dihydrofolate reductase (affinity for the bacterial enzyme is very high), disrupting the formation of tetrahydrofolic acid (a precursor of purines and pyrimidines) from dihydrofolic acid. So, sulfonamides and trimethoprim act in synergy, blocking different stages of one process - the synthesis of purines and pyrimidines.

5-Nitroimidazoles (metronidazole, tinidazole) have a selective bactericidal effect against bacteria whose enzyme systems are capable of reducing the nitro group. Active reduced forms of these drugs, by disrupting DNA replication and protein synthesis, inhibit tissue respiration.

Rifampicin (an anti-tuberculosis drug) specifically inhibits RNA synthesis.

Antifungal and antiviral agents have some similarities in their mechanisms of action. Derivatives of imidazole and triazole inhibit the synthesis of ergosterol, the main structural component

nent of the fungal cell wall, and polyene antibacterial drugs (amphotericin, nystatin) bind to it. Flucytosine (an antifungal drug) blocks the synthesis of fungal DNA. Many antiviral drugs (for example, acyclovir, idoxuridine, zidovudine - nucleoside analogues) also inhibit the synthesis of viral DNA and

N-cholinergic receptors of neuromuscular synapses of helminths are target molecules of such anthelmintic drugs as pyrantel and levamisole. Stimulation of these receptors causes total spastic paralysis.

The nature, strength and duration of the action of drugs

The duration, strength and method of interaction between the drug and the target molecule characterizes the pharmacological response (as a rule, due to the direct action of the drug, less often - a change in the conjugated system, and only in isolated cases is a reflex pharmacological response recorded).

The main effect of drugs is the effect of the substance used in the treatment of this patient. Other pharmacological effects of the considered drug are called secondary (or minor). Functional disorders caused by taking the drug are considered as undesirable reactions (see chapter 4 "Side effects of drugs"). One and the same effect in one case can be primary, and in another - secondary.

There are generalized or local (local) actions of drugs. Local effects are observed when using ointments, powders or drugs taken orally, not absorbed in the gastrointestinal tract, or, conversely, well absorbed, but concentrated in one organ. In most cases, when a drug penetrates into the biological fluids of the body, its pharmacological effect can form anywhere in the body.

The ability of many drugs to act in monotherapy on various levels of regulation and processes of cellular metabolism simultaneously in several functional systems or organs proves the polymorphism of their pharmacological effect. On the other hand, such a large variety of targets at all levels of regulation explains the same pharmacological effect of drugs with different chemical structures.

The chaotic movement of molecules allows the drug to be close to a certain area (with a high affinity for receptors); at the same time, the desired effect is achieved even with the appointment of low concentrations of drugs. With an increase in the concentration of drug molecules,

they react with the active centers of other receptors (for which they have a lower affinity); as a result, the number of pharmacological effects increases, and their selectivity also disappears. For example, β 1 -blockers in small doses inhibit only β 1 -adrenergic receptors. However, with an increase in the dose of β 1 -blockers, their selectivity disappears, while blockade of all β-adrenergic receptors is noted. A similar picture is observed with the appointment of β-agonists. Thus, with an increase in the dose of drugs, along with some increase in the clinical effect, an increase in the number of side effects is always recorded, and significantly.

The state of the target molecule (both in the main and in the conjugated system) must be taken into account when predicting and evaluating the effectiveness of drug action. Often, the predominance of side effects over the main action is due to a violation of the physiological balance due to the nature of the disease or the individual characteristics of the patient.

Moreover, drugs themselves can change the sensitivity of target molecules by varying the rate of their synthesis or degradation or inducing the formation of various target modifications under the influence of intracellular factors - all this leads to a change in the pharmacological response.

According to the pharmacological effects, drugs can be divided into two groups - substances with specific and non-specific effects. Non-specific drugs include drugs that cause the development of a wide range of pharmacological effects by influencing various biological support systems. This group of drugs includes, first of all, substrate substances: vitamin complexes, glucose and amino acids, macroelements and microelements, as well as plant adaptogens (for example, ginseng and eleutherococcus). Due to the lack of clear boundaries that determine the main pharmacological effect of these drugs, they are prescribed to a large number of patients with various diseases.

If a drug acts (as an agonist or antagonist) on the receptor apparatus of certain systems, its effect is considered as specific. This group of drugs includes antagonists and agonists of various subtypes of adrenoreceptors, cholinergic receptors, etc. The organ location of the receptors does not affect the effect produced by drugs with a specific action. Therefore, despite the specificity of the action of these drugs, various pharmacological responses are recorded. So, acetylcholine causes contraction of the smooth muscles of the bronchi, the digestive tract, increases the secretion of the salivary glands. Atropine has the opposite effect. Voter-

The specificity or selectivity of the action of drugs is noted only when the activity of the system changes only in a certain part of it or in one organ. For example, propranolol blocks all β-adrenergic receptors of the sympathoadrenal system. Atenolol, a selective β 1 -blocker, blocks only β 1 -adrenergic receptors of the heart and does not affect β 2 -adrenergic receptors of the bronchi (when using small doses). Salbutamol selectively stimulates β 2 -adrenergic receptors of the bronchi, having a slight effect on β 1 -adrenergic receptors of the heart.

Selectivity (selectivity) of the action of drugs - the ability of a substance to accumulate in the tissue (depends on the physico-chemical properties of drugs) and produce the desired effect. Selectivity is also due to the affinity for the considered morphological link (taking into account the structure of the cell membrane, the characteristics of cell metabolism, etc.). Large doses of selectively acting drugs most often affect the entire system, but cause a pharmacological response corresponding to the specific action of drugs.

If the bulk of the receptors interacts with drugs, then a rapid onset of the pharmacological effect and its greater severity are noted. The process occurs only at high drug affinity (its molecule may have a structure similar to that of a natural agonist). The activity of the drug and the duration of its action in most cases are proportional to the rate of formation and dissociation of the complex with the receptor. With repeated administration of drugs, a decrease in the effect (tachyphylaxis) is sometimes recorded, tk. not all receptors were released from the previous dose of the drug. A decrease in the severity of the effect occurs in the case of depletion of receptors.

Reactions recorded during the administration of drugs

Expected pharmacological response.

Hyperreactivity - increased sensitivity of the body to the drug used. For example, when the body is sensitized with penicillins, their repeated administration can lead to an immediate hypersensitivity reaction or even to the development of anaphylactic shock.

Tolerance - a decrease in sensitivity to the applied drugs. For example, with uncontrolled and prolonged use of β 2 -agonists, tolerance to them increases, and the pharmacological effect decreases.

Idiosyncrasy - individual excessive sensitivity (intolerance) to this drug. For example, the cause of idiosyncrasy may be a genetically determined lack of

tvie enzymes that metabolize this substance (see Chapter 7 "Clinical pharmacogenetics").

Tachyphylaxis is a rapidly developing tolerance. To some drugs, for example, to nitrates (with their continuous and prolonged use), tolerance develops especially quickly; in this case, the drug is replaced or its dose is increased.

Estimating the time of action of drugs, it is necessary to allocate the latent period, the maximum action, the retention time of the effect and the aftereffect time.

The time of the latent period of drugs, especially in urgent situations, determines their choice. So, in some cases, the latent period is seconds (sublingual form of nitroglycerin), in others - days and weeks (aminoquinoline). The duration of the latent period may be due to the constant accumulation of drugs (aminoquinoline) at the site of its impact. Often, the duration of the latent period depends on the mediated mechanism of action (the hypotensive effect of β-blockers).

The retention time of the effect is an objective factor that determines the frequency of administration and the duration of the use of drugs.

Subdividing drugs according to pharmacological effects, it is necessary to take into account that the same symptom is based on different mechanisms of action. An example is the hypotensive effect of drugs such as diuretics, β-blockers, slow calcium channel blockers (different mechanisms of action produce the same clinical effect). This fact is taken into account when choosing drugs or their combinations when conducting individual pharmacotherapy.

There are factors that affect the speed of the onset of the effect, its strength and duration when using medicinal substances.

Speed, method of administration and dose of drug interacting with the receptor. For example, an intravenous bolus of 40 mg of furosemide produces a faster and more pronounced diuretic effect than 20 mg of the drug administered intravenously or 40 mg of a diuretic taken orally.

Severe course of the disease and associated organic lesions of organs and systems. Age aspects also have a great influence on the functional state of the main systems.

Interaction of drugs used (see Chapter 5 "Drug Interactions").

It is important to know that the use of some drugs is justified only if there is an initial pathological change in the system or target acceptors. So, antipyretic drugs (antipyretics) reduce the temperature only with fever.

2. Local and resorptive action of drugs

The action of a substance, manifested at the site of its application, is called local. For example, enveloping agents cover the mucous membrane, preventing irritation of the endings of the afferent nerves. However, a truly local effect is very rare, since substances can either be partially absorbed or have a reflex effect.

The action of a substance that develops after its absorption and entry into the general circulation, and then into the tissues, is called resorptive. The resorptive effect depends on the route of administration of the drug and its ability to penetrate biological barriers.

With local and resorptive action, drugs have either a direct or reflex effect. Direct influence is realized at the place of direct contact of the substance with the tissue. With reflex action, substances affect extero- or interoreceptors, so the effect is manifested by a change in the state of either the corresponding nerve centers or executive organs. Thus, the use of mustard plasters in the pathology of the respiratory organs reflexively improves their trophism (through the exteroreceptors of the skin).

Lecture 6. Basic issues of pharmacodynamics (part 1)

The main task of pharmacodynamics is to find out where and how medicinal substances act, causing certain effects, that is, to establish targets with which drugs interact.

1. Drug targets

The targets of drugs are receptors, ion channels, enzymes, transport systems, and genes. Receptors are called active groups of macromolecules of substrates with which a substance interacts. Receptors that provide the manifestation of the action of a substance are called specific.

There are 4 types of receptors:

receptors that directly control the function of ion channels (H-cholinergic receptors, GABA A receptors);

receptors coupled to the effector through the system "G-proteins-secondary transmitters" or "G-proteins-ion channels". Such receptors are available for many hormones and mediators (M-cholinergic receptors, adrenergic receptors);

receptors that directly control the function of the effector enzyme. They are directly associated with tyrosine kinase and regulate protein phosphorylation (insulin receptors);

receptors for DNA transcription. These are intracellular receptors. They interact with steroid and thyroid hormones.

The affinity of a substance for a receptor, leading to the formation of a “substance-receptor” complex with it, is denoted by the term “affinity”. The ability of a substance, when interacting with a specific receptor, to stimulate it and cause one or another effect is called internal activity.

2. The concept of agonist and antagonist substances

Substances that, when interacting with specific receptors, cause changes in them, leading to a biological effect, are called agonists. The stimulatory effect of an agonist on receptors can lead to activation or inhibition of cell function. If an agonist, interacting with receptors, causes the maximum effect, then this is a full agonist. In contrast to the latter, partial agonists, when interacting with the same receptors, do not cause the maximum effect.

Substances that bind to receptors but do not stimulate them are called antagonists. Their internal activity is zero. Their pharmacological effects are due to antagonism with endogenous ligands (mediators, hormones), as well as with exogenous agonist substances. If they occupy the same receptors with which agonists interact, then we are talking about competitive antagonists; if other parts of the macromolecule that are not related to a specific receptor, but are interconnected with it, then they speak of non-competitive antagonists.

If a substance acts as an agonist at one receptor subtype and as an antagonist at another, it is referred to as an agonist-antagonist.

So-called non-specific receptors are also isolated, by binding to which substances do not cause an effect (blood plasma proteins, mucopolysaccharides of connective tissue); they are also called places of non-specific binding of substances.

The interaction "substance - receptor" is carried out due to intermolecular bonds. One of the strongest types of bond is a covalent bond. It is known for a small number of drugs (some anti-blastoma agents). Less persistent is the more common ionic bond, typical of ganglionic blockers and acetylcholine. An important role is played by van der Waals forces (the basis of hydrophobic interactions) and hydrogen bonds.

Depending on the strength of the “substance-receptor” bond, a reversible action, characteristic of most substances, and an irreversible action (in the case of a covalent bond) are distinguished.

If a substance interacts only with functionally unambiguous receptors of a certain localization and does not affect other receptors, then the action of such a substance is considered selective. The basis of the selectivity of action is the affinity (affinity) of the substance for the receptor.

Ion channels are another important target for drugs. Of particular interest is the search for blockers and activators of Ca 2+ channels with a predominant effect on the heart and blood vessels. In recent years, substances that regulate the function of K+ channels have attracted much attention.

Enzymes are important targets for many drugs. For example, the mechanism of action of non-steroidal anti-inflammatory drugs is due to inhibition of cyclooxygenase and a decrease in the biosynthesis of prostaglandins. The antiblastoma drug methotrexate blocks dihydrofolate reductase, preventing the formation of tetrahydrofolate, which is necessary for the synthesis of the purine nucleotide thymidylate. Acyclovir inhibits viral DNA polymerase.

Another possible drug target is transport systems for polar molecules, ions, and small hydrophilic molecules. One of the latest achievements in this direction is the creation of propion pump inhibitors in the gastric mucosa (omeprazole).

Genes are considered important targets for many drugs. Research in the field of gene pharmacology is becoming more and more widespread.

Lecture 7. Dependence of the pharmacotherapeutic effect on the properties of drugs and the conditions for their use

1. Chemical structure

I. chemical structure, physico-chemical and physical properties of medicines. For effective interaction of a substance with a receptor, such a structure of the drug is necessary that ensures the closest contact with the receptor. The strength of intermolecular bonds depends on the degree of convergence of a substance with a receptor. For the interaction of a substance with a receptor, their spatial correspondence, i.e., complementarity, is especially important. This is confirmed by differences in the activity of stereoisomers. If a substance has several functionally active groups, then the distance between them must be taken into account.

Many quantitative and qualitative characteristics of the action of a substance also depend on such physical and physico-chemical properties as solubility in water and lipids; for powdered compounds, the degree of their grinding is very important, for volatile substances - the degree of volatility, etc.

2. Doses and concentrations

II. Dose dependent(concentration) change the speed of development of the effect, its severity, duration, and sometimes the nature of the action. Usually, with increasing dose, the latent period decreases and the severity and duration of the effect increase.

dose called the amount of the substance at one time (single dose). Indicate the dose in grams or fractions of a gram. The minimum doses at which drugs cause an initial biological effect are called threshold, or minimum, effective doses. In practical medicine, average therapeutic doses are most often used, in which drugs in the vast majority of patients have the necessary pharmacotherapeutic effect. If during their appointment the effect is not sufficiently pronounced, the dose is increased to the highest therapeutic dose. In addition, toxic doses are distinguished, in which substances cause toxic effects dangerous for the body, and lethal doses. In some cases, the dose of the drug for the course of treatment (course dose) is indicated. If there is a need to quickly create a high concentration of a medicinal substance in the body, then the first dose (shock) exceeds the subsequent ones.

3. Reuse of drugs Chemical structure

III. Increasing the effect of a number of substances associated with their ability to accumulate. By material cumulation they mean the accumulation of a pharmacological substance in the body. This is typical for long-acting drugs that are slowly excreted or are strongly bound in the body (for example, some cardiac glycosides from the digitalis group). Accumulation of the substance during its repeated use may be the cause of the development of toxic effects. In this regard, it is necessary to dose such drugs taking into account cumulation, gradually reducing the dose or increasing the intervals between doses of the drug.

Examples of functional cumulation are known, in which the effect, and not the substance, is accumulated. So, with alcoholism, increasing changes in the central nervous system lead to the appearance of delirium tremens. In this case, the substance (ethyl alcohol) is rapidly oxidized and does not linger in the tissues. In this case, only neurotropic effects are summed up.

Reducing the effectiveness of substances with their repeated use - addiction (tolerance)- observed when using various drugs (analgesics, antihypertensives and laxatives). It may be associated with a decrease in the absorption of a substance, an increase in the rate of its inactivation and (or) an increase in excretion, a decrease in the sensitivity of receptors to it, or a decrease in their density in tissues. In case of addiction, to obtain the initial effect, the dose of the drug must be increased or one substance replaced with another. With the latter option, it should be borne in mind that there is cross-addiction to substances that interact with the same receptors. A special type of addiction is tachyphylaxis - addiction that occurs very quickly, sometimes after a single dose of the drug.

In relation to some substances (usually neurotropic), their repeated administration develops drug dependence. It is manifested by an irresistible desire to take a substance, usually with the aim of improving mood, improving well-being, eliminating unpleasant experiences and sensations, including those that occur during the abolition of substances that cause drug dependence. In the case of mental dependence, stopping the administration of the drug (cocaine, hallucinogens) causes only emotional discomfort. When taking certain substances (morphine, heroin), physical dependence develops. Cancellation of the drug in this case causes a serious condition, which, in addition to sudden mental changes, manifests itself in various, often severe somatic disorders associated with dysfunction of many body systems, up to death. This is the so-called withdrawal syndrome.

Lecture 8. Interaction of drugs (part 1)

1. The main types of drug interactions

With the simultaneous appointment of several medicinal substances, their interaction with each other is possible, leading to a change in the severity and nature of the main effect, its duration, as well as to an increase or decrease in side and toxic effects. Drug interactions are usually classified into pharmacological And pharmaceutical.

Pharmacological interaction is based on changes in the pharmacokinetics and pharmacodynamics of drugs, chemical and physico-chemical interactions of drugs in body media.

Pharmaceutical interaction associated with combinations of various drugs, often used to enhance or combine effects useful in medical practice. However, when combining substances, an unfavorable interaction can also occur, which is referred to as drug incompatibility. Incompatibility is manifested by a weakening, complete loss or change in the nature of the pharmacotherapeutic effect, or an increase in side or toxic effects. This occurs when two or more drugs are given at the same time. (pharmacological incompatibility). Incompatibility is also possible during the manufacture and storage of combined preparations. (pharmaceutical incompatibility).

2. Pharmacological interaction

I. The pharmacokinetic type of interaction can manifest itself already at the stage of absorption of the substance, which can change for various reasons. So, in the digestive tract, substances can be bound by adsorbents (activated carbon, white clay) or anion-exchange resins (cholestyramine), the formation of inactive chelate compounds or complexones (according to this principle, antibiotics of the tetracycline group interact with iron, calcium and magnesium ions). All these interaction options interfere with the absorption of drugs and reduce their pharmacotherapeutic effects. For the absorption of a number of substances from the digestive tract, the pH value of the medium is important. Thus, by changing the reaction of digestive juices, one can significantly influence the rate and completeness of the absorption of weakly acidic and weakly alkaline compounds.

Changes in the peristalsis of the digestive tract also affect the absorption of substances. For example, an increase in intestinal motility by cholinomimetics reduces the absorption of digoxin. In addition, examples of the interaction of substances at the level of their transport through the intestinal mucosa are known (barbiturates reduce the absorption of griseofulvin.

Inhibition of enzyme activity can also affect absorption. So, difenin inhibits folate deconjugation and disrupts the absorption of folic acid from food products. As a result, folic acid deficiency develops. Some substances (almagel, vaseline oil) form layers on the surface of the mucous membrane of the digestive tract, which can somewhat hinder the absorption of drugs.

The interaction of substances is possible at the stage of their transport with blood proteins. In this case, one substance can displace another from the complex with blood plasma proteins. So, indomethacin and butadione release anticoagulants of indirect action from the complex with plasma proteins, which increases the concentration of free anticoagulants and can lead to bleeding.

Some medicinal substances are able to interact at the level of biotransformation of substances. There are drugs that increase (induce) the activity of microsomal liver enzymes (phenobarbital, difenin, etc.). Against the background of their action, the biotransformation of many substances proceeds more intensively.

This reduces the severity and duration of their effect. It is also possible the interaction of drugs associated with the inhibitory effect on microsomal and non-microsomal enzymes. Thus, the anti-gout drug allopurinol increases the toxicity of the anticancer drug mercaptopurine.

The excretion of medicinal substances can also change significantly with the combined use of substances. Reabsorption in the renal tubules of weakly acidic and weakly alkaline compounds depends on the pH value of the primary urine. By changing its reaction, it is possible to increase or decrease the degree of ionization of the substance. The lower the degree of ionization of a substance, the higher its lipophilicity and the more intense the reabsorption in the renal tubules. More ionized substances are poorly reabsorbed and more excreted in the urine. For alkalinization of urine, sodium bicarbonate is used, and for acidification, ammonium chloride is used.

It should be borne in mind that when substances interact, their pharmacokinetics can change at several stages simultaneously.

II. Pharmacodynamic type of interaction. If the interaction is carried out at the level of receptors, then it mainly concerns agonists and antagonists of various types of receptors.

In the case of synergy, the interaction of substances is accompanied by an increase in the final effect. Synergism of medicinal substances can be manifested by simple summation or potentiation of the final effect. The summed (additive) effect is observed by simply adding the effects of each of the components. If, with the introduction of two substances, the total effect exceeds the sum of the effects of both substances, then this indicates potentiation.

Synergism can be direct (if both compounds act on the same substrate) or indirect (with different localization of their action).

The ability of one substance to some extent to reduce the effect of another is called antagonism. By analogy with synergy, it can be direct and indirect.

In addition, synergoantagonism is distinguished, in which some effects of the combined substances are enhanced, while others are weakened.

III. The chemical or physico-chemical interaction of substances in body media is most often used in overdose or acute drug poisoning. In case of an overdose of the anticoagulant heparin, its antidote, protamine sulfate, is prescribed, which inactivates heparin due to electrostatic interaction with it (physicochemical interaction). An example of a chemical interaction is the formation of complexones. So, ions of copper, mercury, lead, iron and calcium bind penicillamine.

Lecture 9. Interaction of drugs (part 2)

1. Pharmaceutical interaction

There may be cases of pharmaceutical incompatibility, in which during the manufacture of drugs and (or) their storage, as well as when mixed in one syringe, the components of the mixture interact and such changes occur, as a result of which the drug becomes unsuitable for practical use. In some cases, new, sometimes unfavorable (toxic) properties appear. Incompatibility may be due to insufficient solubility or complete insolubility of substances in the solvent, coagulation of dosage forms, separation of the emulsion, dampness and melting of powders due to their hygroscopicity, undesirable absorption of active substances is possible. In incorrect prescriptions, as a result of chemical interaction of substances, a precipitate sometimes forms or the color, taste, smell and consistency of the dosage form change.

2. The importance of the individual characteristics of the body and its condition for the manifestation of the action of drugs

I. Age. Drug sensitivity varies with age. In this regard, perinatal pharmacology, which studies the effects of drugs on the fetus (24 weeks before birth and up to 4 weeks after birth), has emerged as an independent discipline. The section of pharmacology that studies the features of the action of drugs on the child's body is called pediatric pharmacology.

For medicinal substances (except for poisonous and potent ones), there is a simplified rule for calculating substances for children of different ages, based on the fact that for each year a child needs 1/20 of an adult dose.

In the elderly and senile age, the absorption of medicinal substances slows down, their metabolism proceeds less efficiently, and the rate of excretion of drugs by the kidneys decreases. Geriatric pharmacology is engaged in elucidating the features of the action and use of drugs in elderly and senile people.

II. Floor. To a number of substances (nicotine, strychnine), males are less sensitive than females.

III. genetic factors. Drug sensitivity can be genetically determined. For example, with a genetic deficiency of blood plasma cholinesterase, the duration of action of the muscle relaxant ditilin sharply increases and can reach 6-8 hours (under normal conditions - 5-7 minutes).

Examples of atypical reactions to substances (idiosyncrasy) are known. For example, 8-aminoquinoline antimalarials (primaquine) can cause hemolysis in individuals with a genetic enzymopathy. Other substances with a potential hemolytic effect are also known: sulfonamides (streptocide, sulfacyl sodium), nitrofurans (furazolidone, furadonin), non-narcotic analgesics (aspirin, phenacetin).

IV. Body condition. Antipyretic drugs act only with fever (with normothermia, they are ineffective), and cardiac glycosides - only against the background of heart failure. Diseases accompanied by impaired liver and kidney function alter the biotransformation and excretion of substances. The pharmacokinetics of drugs also changes during pregnancy and obesity.

v. The value of circadian rhythms. The study of the dependence of the pharmacological effect of drugs on daily periodicity is one of the main tasks of chronopharmacology. In most cases, the most pronounced effect of substances is observed during the period of maximum activity. So, in humans, the effect of morphine is more pronounced at the beginning of the second half of the day than in the morning or at night.

Pharmacokinetic parameters also depend on circadian rhythms. The greatest absorption of griseofulvin occurs at about 12 noon. During the day, the intensity of the metabolism of substances, the function of the kidneys and their ability to excrete pharmacological substances change significantly.